INPULSIS
NEJM 2014
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INPULSIS-1 and INPULSIS-2 were replicate, 52-week, randomized, double-blind, placebo-controlled phase 3 trials evaluating nintedanib 150 mg twice daily in idiopathic pulmonary fibrosis. Nintedanib significantly slowed the annual rate of FVC decline versus placebo in both trials (between-group differences ~100–125 ml/year), consistent with a slowing of disease progression.
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Nintedanib consistently slowed lung-function decline in IPF by ~100–125 ml/year versus placebo over 52 weeks, supporting a disease-modifying effect on FVC slope.
Acute exacerbations are uncommon and difficult to measure. INPULSIS initially did not show a protective effect against AE-IPF; however, this protective effect was apparent after AE-IPF events were adjudicated. Additional real-world data are suggestive of a reduction in AE-IPF from nintedanib use.
Diarrhea is common with nintedanib but typically manageable with antidiarrheals and temporary dose reduction/interruption; monitor liver enzymes given higher rates of transaminase elevations.
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Background
Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis.
Methods
We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period.
Results
A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was −114.7 ml with nintedanib versus −239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and −113.6 ml with nintedanib versus −207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2.
Conclusions
In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.)